EP0362695A1 - Dérivés de pyrrolocarbazole, procédés de leur préparation et leur application comme médicaments - Google Patents

Dérivés de pyrrolocarbazole, procédés de leur préparation et leur application comme médicaments Download PDF

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Publication number
EP0362695A1
EP0362695A1 EP89117957A EP89117957A EP0362695A1 EP 0362695 A1 EP0362695 A1 EP 0362695A1 EP 89117957 A EP89117957 A EP 89117957A EP 89117957 A EP89117957 A EP 89117957A EP 0362695 A1 EP0362695 A1 EP 0362695A1
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general formula
compounds
group
carbon atoms
hydrogen
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EP89117957A
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German (de)
English (en)
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EP0362695B1 (fr
Inventor
Jürgen Dr. Kleinschroth
Johannes Dr. Hartenstein
Christoph Dr. Schächtele
Claus Dr. Rudolph
David James Dr. Dooley
Günter Dr. Weinheimer
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Goedecke GmbH
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Goedecke GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to new pyrrolocarbazole derivatives of the general formula I. in which A and B or C and D are either the same and represent hydrogen or together form a carbonyl oxygen atom, or are different, one of the radicals of A and B or of C and D being hydrogen and the other of the two radicals being a hydroxyl group means, with the proviso that at least one of the combinations A and B or C and D together form a carbonyl oxygen atom, R1, R2 and R3 are either the same or different and each represents a trifluoromethyl group for hydrogen, a halogen atom, in particular fluorine, chlorine or bromine , an alkyl group with 1 to 4 carbon atoms, a nitro group, an amino group, unsubstituted or substituted by an alkyl group with 1 to 4 carbon atoms or a benzyl group, an alkoxy group with 1 to 4 carbon atoms, a hydroxy group, an acyl group with 1 to 4 carbon atoms or
  • Preferred compounds of the general formula I are those in which R 1, R 2 and R 3 are either the same or different and are hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxy-nitro, methyl, ethyl, n-propyl, isopropyl -, n-Butyl, amino, methoxy, ethoxy, aminoethoxy, aminopropoxy, dimethylaminoethoxy, dimethylaminopropoxy, diethylaminoethoxy, N-benzyl-N-methylaminoethoxy, N-benzyl-N-methylaminopropoxy, dimethylaminohydroxypropoxy -, Piperidinoethoxy-, Piperidinopropoxy-, Pyrrolidinoethoxy-, Pyrrolidinopropoxy-, Morpholinoethoxy-, Morpholinopropoxy-, Pyrrolidinylmethoxy-, Piperidinylmethoxy-, N-Methyl
  • the compounds I are prepared by one of the processes described below:
  • the compounds of the general formula III are dehydrated to give compounds IV by customary processes, for example using 2,3-dichloro-5,6-dicyan-p-benzoquinone (DDQ), sulfur or palladium on activated carbon.
  • DDQ 2,3-dichloro-5,6-dicyan-p-benzoquinone
  • DDQ 2,3-dichloro-5,6-dicyan-p-benzoquinone
  • DDQ 2,3-dichloro-5,6-dicyan-p-benzoquinone
  • sulfur or palladium on activated carbon palladium on activated carbon.
  • phosphorus (III) compounds such as triphenylphosphine or triethylphosphite in a suitable inert solvent
  • Compounds of the general formula VII, in which R4 represents one of the above-defined aminoalkyl groups having 1 to 12 C atoms or a cyanoalkyl group having 2 to 4 C atoms, are preferably by aminoalkylation or cyanoalkylation of compounds of the general formula VII, in which R4 represents hydrogen, prepared by known processes of aminoalkylation or cyanoalkylation of indole derivatives.
  • the trans isomers of compounds of general formula VII are converted into the compounds of general formula VIII by heating with maleimide in a suitable solvent.
  • the cis isomers of compounds of the general formula VII or mixtures of isomers are converted into the compounds of the general formula VIII with the addition of catalysts such as aluminum trichloride with maleimide in a suitable solvent.
  • Catalyzed aluminum trichloride with maleimide in a suitable solvent.
  • the compounds of the general formula VIII are dehydrated to the new pyrrolocarbazole derivatives of the general formula Ib by conventional processes, for example with 2,3-dichloro-5,6-dicyan-p-benzoquinone, palladium on activated carbon, sulfur or sodium nitrite in glacial acetic acid.
  • Lactams of the general formula I in which either A and B or C and D are hydrogen and the other two radicals together form a carbonyl oxygen atom (compounds Ic) by reduction of imides of the general formulas Ia or Ib, in which both A and B as well as C and D form a carbonyl oxygen atom, prepared according to Reaction Scheme III.
  • Zinc amalgam / hydrogen chloride gas in C1-C4 alcohols or zinc amalgam in glacial acetic acid or zinc in glacial acetic acid are used as preferred reducing agents.
  • the partially occurring regioisomer mixtures of compounds Ic can be separated by conventional methods such as crystallization or chromatography.
  • the carbonyl oxygen atom which is formed by C and D is preferably reduced under the stated reaction conditions.
  • Hydroxylactams of the general formula I in which either A and B or C and D together form a carbonyl oxygen atom, one of the other two radicals is hydrogen and the other is a hydroxyl group (compounds Id) are also according to reaction scheme IV by reduction of imides of the general formulas Ia or Ib.
  • the partially occurring regioisomer mixtures of compounds Id can be separated by conventional methods of crystallization or chromatography.
  • Lactams of the general formula Ic, in which R4 is hydrogen can by reaction with compounds R 4' -X, in which R 4 ', with the exception of hydrogen, has the meanings given for R4 and X preferably for halogen , in particular iodine, bromine or chlorine, is, according to reaction scheme V, in the presence of bases such as hydrides, carbonates, hydroxides, oxides or alkoxides of the alkali or alkaline earth metals, or of organolithium compounds in a known manner on the indole nitrogen atom to lactams of the general formula Ic ⁇ be alkylated.
  • bases such as hydrides, carbonates, hydroxides, oxides or alkoxides of the alkali or alkaline earth metals, or of organolithium compounds in a known manner on the indole nitrogen atom to lactams of the general formula Ic ⁇ be alkylated.
  • Unsubstituted or substituted aminoalkyl groups with up to 12 carbon atoms which are particularly suitable for R4 are unsubstituted aminoalkyl groups, such as a 2-aminoethyl, a 3-aminopropyl or a 1-amino-2-propyl radical, N, N-dialkylaminoalkyl or N, N-alkylbenzylaminoalkyl groups with C1-C4-alkyl substituents on the nitrogen atoms and 1-4 C-atoms in the alkyl chain, where the alkyl chains can be substituted by further C1-C4-alkyl radicals, a hydroxy or a methoxy group, in particular a 2-dimethylaminoethyl , 3-dimethylamino-1-propyl-, 3-dimethylamino-2-propyl-, 2-diethylaminoethyl-, 2- [N-benzyl-N-methylamino] ethyl
  • radicals particularly suitable for R4 are straight-chain or branched alkyl groups with 1 to 4 carbon atoms, in particular methyl, ethyl, n-propyl, isopropyl and n-butyl, cyanoalkyl groups with 2 or 3 carbon atoms, in particular cyanomethyl and 2-cyanoethyl, Alkoxycarbonylalkyl groups with up to 7 carbon atoms, in particular 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl and methoxycarbonylmethyl.
  • Preferred radical combinations for R 1 and R 2 are:
  • R1 and R2 are hydrogen or R1 is hydrogen and R2 is 2-methyl, 2-chloro, 3-chloro, 4-chloro, 2-bromo, 2-fluoro, 2-trifluoromethyl, 2-methoxy, 3-methoxy, 4-methoxy, 2-amino, 2-nitro, 2-hydroxy or 2- (3-dimethylaminopropoxy) group or R1 is 2-nitro and R2 is 5-methoxy.
  • Lactams or hydroxylactams of the general formula I, in which the radicals A and B are different from the radicals C and D, can also be used as regioisomer mixtures, or, as already described, separated by known methods such as crystallization or chromatography.
  • Hydroxylactams of the general formula I in which one of the radicals A, B, C or D represents a hydroxyl group and is bonded to a chiral center, or compounds of the general formula I which have a chiral center in the radicals R1, R2, R3 or R4 can be used as stereoisomer mixtures or in the form of the enantiomers.
  • the enantiomers can be obtained by the conventional methods used for optical separation of stereoisomers.
  • Basic compounds of the general formula I which have a basic center on R1, R2, R3 or R4 are preferably converted into crystalline, pharmacologically acceptable salts for the purpose of purification and for galenical reasons.
  • the salts are obtained in the usual way by neutralizing the bases with appropriate inorganic or organic acids. Examples of acids are hydrochloric acid, sulfuric acid, Phosphoric acid, hydrobromic acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, salicylic acid, ascorbic acid, malonic acid, fumaric acid, oxalic acid or succinic acid.
  • the acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol or 2-propanol or a lower ketone such as acetone or 2-butanone or an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane.
  • an organic solvent for example a lower alcohol such as methanol, ethanol or 2-propanol or a lower ketone such as acetone or 2-butanone or an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane.
  • the compounds according to the invention are potent inhibitors of protein kinases such as protein kinase C.
  • protein kinases such as protein kinase C.
  • the compound of Example 2.a in the enzyme assay of the protein kinase C activated with phosphatidylserine and diacylglycerol showed a 50% inhibition at a concentration of 0.58 ⁇ mol / l.
  • the test was carried out in accordance with EP-OS-0 255 126 (inhibition of protein kinase C).
  • Protein kinase C plays an important key role in intracellular signal transduction and is closely linked to the regulation of contractile, secretory and proliferative processes. Because of these properties, the compounds according to the invention can be used for the prevention and / or treatment of heart and vascular diseases such as thrombosis, arteriosclerosis, hypertension, of inflammatory processes, allergies, cancer and certain degenerative damage to the central nervous system, and for the treatment of viral diseases.
  • the compounds can be administered enterally or parenterally in doses of 1 to 500 mg / kg, preferably 1 to 50 mg / kg, in the respectively suitable formulation.
  • the compounds of general formula I according to the invention can be administered orally or parenterally in liquid or solid form.
  • Water is used as the injection solution, which is the usual solution for injection solutions Contains additives such as stabilizers, solubilizers or buffers.
  • Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediamine tetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.
  • Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycol);
  • Preparations suitable for oral administration can optionally contain additional flavors and / or sweeteners.
  • the (E, E) -1- (2-nitrophenyl) -4-phenyl-1,3-butadiene used as the starting product is analogous to Tetrahedron Lett. 1983, 1441 obtained by isomerization with iodine in toluene of the (E, E) and (E, Z) isomer mixture formed in the reaction of 2-nitrobenzyltriphenylphosphonium bromide with trans-cinnamaldehyde.
  • 1,2,3,3a, 4,5,6,10c-octahydro-1,3-dioxo-4-phenyl-pyrrolo [3,4-c] carbazole are obtained in the form of colorless crystals of mp 212-215 ° C.
  • (Z) -1- (2-indolyl) -2-phenylethylene is obtained in the form of a pale yellow oil which crystallizes on drying in vacuo. The fraction with Rf 0.2 is evaporated, the residue is stirred with cyclohexane and the crystals formed are filtered off.
  • (E) -1- (2-indolyl) -2-phenylethylene is obtained in the form of almost colorless crystals, mp. 205-206 ° C. According to the literature (Arch. Pharm. 310, 975, 1977), the 2-indolaldehyde is prepared from 2-indolecarboxylic acid esters.
  • Example 2 a 0.8 g (2.13 mmol) of 4- (2-chlorophenyl) -6-ethyl-1,2,3,6-tetrahydro-1,3-dioxopyrrolo [3,4-c] carbazole (Example 2 a) are suspended in 20 ml of 90% methanol, a solution of 0.16 g (4.23 mmol) of sodium borohydride in 5 ml of methanol is added dropwise with vigorous stirring and the mixture is stirred at room temperature for 5 days. The excess sodium borohydride is decomposed with acetic acid, the solvent is distilled off and the crystalline residue is chromatographed on silica gel using toluene / ethyl acetate 1: 1.
  • the 6- (3-dimethylaminopropyl) -1,2,3,3a, 4,5,6,10c-octahydro-1,3-dioxo-4-phenyl-pyrrolo [3,4-c] carbazole used as the starting product becomes prepared by reacting (E) -1- [1- (3-dimethylaminopropyl) -2-indolyl] -2-phenylethylene with maleimide in toluene analogously to Example 1, process B.
  • the 6- (2-cyanoethyl) -1,2,3,3a, 4,5,6,10c-octahydro-4- (2-methylphenyl) -1,3-dioxopyrrolo [3,4- c] carbazole is prepared by reacting (E) -1- [1- (2-cyanoethyl) -2-indolyl] -2- (2-methylphenyl) ethylene with maleimide in toluene analogously to Example 1, process B.

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EP89117957A 1988-09-29 1989-09-28 Dérivés de pyrrolocarbazole, procédés de leur préparation et leur application comme médicaments Expired - Lifetime EP0362695B1 (fr)

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Application Number Priority Date Filing Date Title
AT89117957T ATE62242T1 (de) 1988-09-29 1989-09-28 Pyrrolocarbazol-derivate, verfahren zu deren herstellung und deren verwendung als arzneimittel.

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DE3833008 1988-09-29
DE3833008A DE3833008A1 (de) 1988-09-29 1988-09-29 Pyrrolocarbozol-derivate, verfahren zu deren herstellung und deren verwendung als arzneimittel

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EP0362695A1 true EP0362695A1 (fr) 1990-04-11
EP0362695B1 EP0362695B1 (fr) 1991-04-03

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US (1) US4912107A (fr)
EP (1) EP0362695B1 (fr)
JP (1) JPH02142791A (fr)
AT (1) ATE62242T1 (fr)
DE (2) DE3833008A1 (fr)
ES (1) ES2029920T3 (fr)
GR (1) GR3001738T3 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0624586A1 (fr) * 1993-05-10 1994-11-17 F. Hoffmann-La Roche Ag Pyroles substituées
EP0695755A1 (fr) * 1994-08-04 1996-02-07 F. Hoffmann-La Roche AG Pyrrolocarbazoles
EP0728758A1 (fr) * 1995-02-27 1996-08-28 F. Hoffmann-La Roche Ag Dérivés de dioxopyrrolo-pyrrole
US5721230A (en) * 1993-05-10 1998-02-24 Hoffmann-La Roche Inc. Substituted pyrroles
WO2003091255A1 (fr) * 2002-04-26 2003-11-06 Warner-Lambert Company Llc Inhibiteurs de checkpoint kinases (wee1 et chk1)
US7094798B1 (en) 2002-04-26 2006-08-22 Pfizer Inc Inhibitors of checkpoint kinases (Wee1 and Chk1)

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US5380746A (en) * 1989-05-05 1995-01-10 Goedecke Aktiengesellschaft Bis-(1H-indol-3-YL)-maleinimide derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
GB2239013B (en) * 1989-11-01 1993-06-02 Toyama Chemical Co Ltd Novel isoindole derivatives and salts thereof,processes for producing the same and antitumor agent comprising the same
US5489608A (en) * 1989-12-21 1996-02-06 Goedecke Aktiengesellschaft Indolocarbazole derivatives and the use thereof
US5418245A (en) * 1990-04-16 1995-05-23 Rhone-Poulenc Rorer International (Holdings) Inc. Styryl-substituted monocyclic and bicyclic heteroaryl compounds which inhibit EGF receptor tyrosine kinase
US5591842A (en) * 1991-11-29 1997-01-07 Banyu Pharmaceutical Co., Ltd. Indolopyrrolocarbazole derivatives
US5668271A (en) * 1991-11-29 1997-09-16 Banyu Pharmaceutical Co., Ltd. Indolopyrrolocarbazole derivatives
DE4243321A1 (de) * 1992-12-21 1994-06-23 Goedecke Ag Aminosäurederivate von Heterocyclen als PKC-Inhibitoren
US5804564A (en) * 1994-05-09 1998-09-08 Banyu Pharmaceutical Co., Ltd. Antitumor indolopyrrolocarbazole derivatives
US5922860A (en) * 1994-05-09 1999-07-13 Banyu Pharmaceutical Co., Ltd. Antitumor indolopyrrolocarbazole derivatives
AU2771395A (en) * 1994-06-14 1996-01-05 Sloan-Kettering Institute For Cancer Research Ceramide-activated protein kinase and methods of use of effectors
US5594009A (en) * 1994-10-14 1997-01-14 Cephalon, Inc. Fused pyrrolocarbazoles
US5475110A (en) * 1994-10-14 1995-12-12 Cephalon, Inc. Fused Pyrrolocarbazoles
US5705511A (en) * 1994-10-14 1998-01-06 Cephalon, Inc. Fused pyrrolocarbazoles
US5591855A (en) * 1994-10-14 1997-01-07 Cephalon, Inc. Fused pyrrolocarbazoles
DE69629341T2 (de) * 1995-03-09 2004-06-09 Kyowa Hakko Kogyo Co., Ltd. Pyrrolocarbazolderivate
US5616724A (en) * 1996-02-21 1997-04-01 Cephalon, Inc. Fused pyrrolo[2,3-c]carbazole-6-ones
WO1998009967A1 (fr) * 1996-09-09 1998-03-12 Kyowa Hakko Kogyo Co., Ltd. Derives de pyrrolocarbazole
US6147109A (en) * 1997-10-14 2000-11-14 The General Hospital Corporation Upregulation of Type III endothelial cell Nitric Oxide Synthase by HMG-CoA reductase inhibitors
US6180597B1 (en) * 1998-03-19 2001-01-30 Brigham And Women's Hospital, Inc. Upregulation of Type III endothelial cell nitric oxide synthase by rho GTPase function inhibitors
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US20060276497A1 (en) 2000-05-09 2006-12-07 Cephalon, Inc. Novel multicyclic compounds and the use thereof
US7122679B2 (en) 2000-05-09 2006-10-17 Cephalon, Inc. Multicyclic compounds and the use thereof
US20050070591A1 (en) * 2001-12-18 2005-03-31 Fumihiko Kanai Indole derivative

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CHEMICAL ABSTRACTS, Band 71, Nr. 5, 4. August 1969, Columbus, Ohio, USA RASHYDIAN et al. "Isoindoline derivatives. I. Synthesis of some diamines of the isoindo- line series" Seite 311, Zusammenfassung- -Nr. 21 972z *
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0624586A1 (fr) * 1993-05-10 1994-11-17 F. Hoffmann-La Roche Ag Pyroles substituées
US5721230A (en) * 1993-05-10 1998-02-24 Hoffmann-La Roche Inc. Substituted pyrroles
CN1048014C (zh) * 1993-05-10 2000-01-05 霍夫曼-拉罗奇有限公司 取代的吡咯类化合物及其制法、药物组合物和用途
EP0695755A1 (fr) * 1994-08-04 1996-02-07 F. Hoffmann-La Roche AG Pyrrolocarbazoles
US5721267A (en) * 1994-08-04 1998-02-24 Syntex (U.S.A.) Inc. Chemotherapeutic pyrrolocarbazole derivatives
CN1051551C (zh) * 1994-08-04 2000-04-19 弗·哈夫曼-拉罗切有限公司 新型吡咯并咔唑衍生物
EP0728758A1 (fr) * 1995-02-27 1996-08-28 F. Hoffmann-La Roche Ag Dérivés de dioxopyrrolo-pyrrole
US5686459A (en) * 1995-02-27 1997-11-11 Hoffmann-La Roche Inc. Dioxopyrrolo pyrrole derivatives
CN1056844C (zh) * 1995-02-27 2000-09-27 弗·哈夫曼-拉罗切有限公司 二氧代吡咯并吡咯衍生物
WO2003091255A1 (fr) * 2002-04-26 2003-11-06 Warner-Lambert Company Llc Inhibiteurs de checkpoint kinases (wee1 et chk1)
US7094798B1 (en) 2002-04-26 2006-08-22 Pfizer Inc Inhibitors of checkpoint kinases (Wee1 and Chk1)

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US4912107A (en) 1990-03-27
ES2029920T3 (es) 1992-10-01
ATE62242T1 (de) 1991-04-15
DE3833008A1 (de) 1990-04-05
DE58900077D1 (de) 1991-05-08
JPH02142791A (ja) 1990-05-31
EP0362695B1 (fr) 1991-04-03
GR3001738T3 (en) 1992-11-23

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